Горденин: Химия, Таралуы және Биологиялық Әсерлері

Hordenine is an alkaloid of the phenethylamine class that occurs naturally in a variety of plants, taking its name from one of the most common, barley (Hordeum species). Chemically, hordenine is the N methyl derivative of N methyltyramine, and the N,N dimethyl derivative of the well known biogenic amine tyramine, from which it is biosynthetically derived and with which it shares some pharmacological properties (see below). as of September 2012, hordenine is widely sold as an ingredient of nutritional supplements, with the claims that it is a stimulant of the central nervous system, and has the ability to promote weight loss by enhancing metabolism. In experimental animals, given sufficiently large doses parenterally (by injection), hordenine does produce an increase in blood pressure, as well as other disturbances of the cardiovascular, respiratory, and nervous systems. These effects are generally not reproduced by oral administration of the drug in test animals, and virtually no scientific reports of the effects of hordenine in human beings have been published.

The first report of the isolation from a natural source of the compound which is now known as hordenine was made by Arthur Heffter in 1894, who extracted this alkaloid from the cactus Anhalonium fissuratus (now reclassified as Ariocarpus fissuratus), naming it "anhalin". Twelve years later, E. Léger independently isolated an alkaloid which he named hordenine from germinated barley (Hordeum vulgare) seeds. Ernst Späth subsequently showed that these alkaloids were identical and proposed the correct molecular structure for this substance, for which the name "hordenine" was ultimately retained. Hordenine is present in a fairly wide range of plants, notably amongst the cacti, but has also been detected in some algae and fungi. It occurs in grasses, and is found at significantly high concentrations in the seedlings of cereals such as barley (Hordeum vulgare) (about 0.2%, or 2000 μg/g), proso millet (Panicum miliaceum) (about 0.2%), and sorghum (Sorghum vulgare) (about 0.1%). Since barley, via its conversion to malt, is used extensively in the production of beer, beer and malt have been examined by several groups of investigators for the presence of hordenine. Citing a 1965 study by McFarlane, Poocharoen reported that beer contained ~ 12–24 mg/L, wort contained about 11–13 mg/L, and malt contained about 67 μg/g of hordenine. The hordenine content of various malts and malt fractions was extensively studied by Poocharoen himself, who also provided a good coverage of related literature up to 1983. This researcher found a mean concentration of hordenine in raw barleyefn|The level of hordenine in ungerminated barley is negligible, but rises as germination (the first part of the "malting" process) proceeds. In comparing literature values for hordenine concentrations in "barley" or barley "malt", therefore, consideration should be made of the age and parts of the plant being analyzed: the figure of about 2,000 μg/g cited in the review by Smith,

Hordenine is biosynthesized by the stepwise N methylation of tyramine, which is first converted to N methyltyramine, and which, in turn is methylated to hordenine. The first step in this sequence is accomplished by the enzyme tyramine N methyltransferase (tyramine methylpherase), but if the same enzyme is responsible for the second methylation that actually produces hordenine is uncertain.

Since the hordenine molecule contains both a basic (amine) and acidic (phenol) functional group, it is amphoteric. The apparent (see original article for discussion) pKas for protonated hordenine are 9.78 (phenolic H) and 10.02 (ammonium H). Common salts are hordenine hydrochloride, R NH3+Cl−, m. p. 178 °C, and hordenine sulfate, (R NH3+)2SO42−, m. p. 211 °C. The "methyl hordenine HCl" which is listed as an ingredient on the labels of some nutritional supplements is in all likelihood simply hordenine hydrochloride, since the "description" of "methyl hordenine HCl" given by virtually all bulk suppliers of this substance corresponds to that for hordenine hydrochloride (or possibly just hordenine). Five regioisomeric compounds would correspond to the name "methyl hordenine HCl", if it were interpreted according to the rules of chemical nomenclature: α methyl hordenine, β methyl hordenine, 2 methyl hordenine, 3 methyl hordenine, and 4 O methyl hordenine each in the form of its HCl salt; N methyl hordenine is better known as the natural product candicine, but is excluded from the possibilities because it is a quaternary ammonium salt that cannot be protonated, hence cannot form a hydrochloride salt.

The first pharmacological study of hordenine to be recorded is that of Heffter, who was also the first to isolate it. Using the sulfate salt (see "Chemistry"), Heffter gave a subcutaneous dose of 0.3 g to a 2.8 kg cat (about 107 mg/kg), and observed no effects besides violent vomiting; the cat behaved normally within 45 mins. He also took a dose of 100 mg orally himself, without experiencing any observable effect. However, the alkaloid was observed to produce a paralysis of the nervous system in frogs. In a subsequent paper, Camus reported that the intravenous (IV) administration of some hundreds of mg of hordenine sulfate to dogs or rabbits caused an increase in blood pressure and changes in the rhythm and force of contraction of the heart, noting also that the drug was not orally active. The cardiovascular and other effects of hordenine were reviewed in detail by Reitschel, writing in 1937. More modern studies were carried out by Frank and coworkers, who reported that IV administration of 2 mg/kg of hordenine to horses produced substantial respiratory distress, increased the rate of respiration by 250%, doubled the heart rate, and caused sweating without changes in basal body temperature or behavior. All effects disappeared within 30 mins. The same dose of hordenine given orally did not produce any of the effects seen after parenteral administration. In a 1995 study, Hapke and Strathmann reported that in dogs and rats, hordenine produced a positive inotropic effect on the heart (i. e. increased the strength of contraction), increased systolic and diastolic blood pressure, and increased the volume of peripheral blood flow. Movements of the gut were inhibited. Additional experiments on isolated tissue lead these investigators to conclude that hordenine was an indirectly acting adrenergic agent that produced its pharmacological effects by releasing stored norepinephrine (NE). Hordenine was found to be a selective substrate for MAO B, from rat liver, with Km = 479 μM, and Vmax = 128 nM/mg protein/h. It was not deaminated by MAO A from rat intestinal epithelium. In contrast to tyramine, hordenine did not produce contraction of isolated rat vas deferens, but a 25 μM concentration of the drug did potentiate its response to submaximal doses of NE, and inhibited its response to tyramine. However, the response to NE of isolated vas deferens taken from rats chronically treated with guanethidine was not affected by hordenine. The investigators concluded that hordenine acted as an inhibitor of NE reuptake in rat vas deferens. In a study of the effects of a large number of compounds on a rat trace amine receptor (rTAR1) expressed in HEK 293 cells, hordenine, at a concentration of 1 μM, had almost identical potency to that of the same concentration of β phenethylamine in stimulating cAMP production through the rTAR1. The potency of tyramine in this receptor preparation was slightly higher than that of hordenine.

LD50 in mice, by intraperitoneal (IP) administration: 299 mg/kg. Other LD50 values given in the literature are: >100 mg/kg (mouse; IP), as HCl salt: 113.5 mg/kg (mouse; route of administration unspecified) Minimum lethal dose (as sulfate salt): 300 mg/kg (dog; IV); 2000 mg/kg (dog; oral); 250 mg/kg (rabbit; IV); 300 mg/kg (guinea pig; IV); 2000 mg/kg (guinea pig; subcutaneous); about 1000 mg/kg (rat; subcutaneous). Although hordenine is capable of reacting with nitrosating agents (e. g. nitrite ion, NO2−) to form the carcinogen N nitrosodimethylamine (NDMA), and was investigated as a possible precursor for the significant amounts of NDMA once found in beer,

The pharmacokinetics of hordenine have been studied in horses. After IV administration of the drug, the α phase T1/2 was found to be about 3 mins., and the β phase T1/2 was about 35 mins. and to caterpillars of Heliothis virescens and Heliothis subflexa; the estimated concentration of hordenine that reduced feeding duration to 50% of control was 0.4M for H. virescens and 0.08M for H. subflexa.

Hordenine has some plant growth inhibiting properties: Liu and Lovett reported that, at a concentration of 50 ppm, it reduced the radicle length in seedlings of white mustard (Sinapis alba) by around 7%; admixture with an equal amount of gramine markedly enhanced this inhibitory effect.